System, for monitoring the concentration of analytes in body fluids

ABSTRACT

The invention concerns a system for monitoring the concentration of analytes in body fluids, in particular in interstitial fluid and comprises a catheter having an implantable region and an outlet opening for withdrawing fluid in particular body fluid. A first and a second analytical zone are contacted sequentially with fluid from the catheter and undergo a detectable change when an analyte is present. The analytical zones can be contacted manually with fluid and also preferably in an automated fashion by means of a device. A system according to the invention additionally has an analytical device for analysing the analytical zones in order to determine the concentration of the analyte on the basis of changes caused by the analyte. A further subject matter of the present invention are catheters for use in systems according to the invention as well as magazines containing test zones.

TECHNICAL FIELD

The present invention is in the field of diagnosis in which body fluidsare withdrawn and analysed for the presence or concentration ofanalytes.

BACKGROUND

Numerous methods are known in the prior art for monitoring analyteconcentrations in body fluids. On the one hand there are systems inwhich blood is withdrawn by a catheter and conveyed to a measuring cell.The document WO 91/16416 which describes an instrument that can becarried on the arm that withdraws blood samples by means of a catheterimplanted in a blood vessel is mentioned as a representative of suchprocedures. The sample liquid is conveyed through an essentially closedchannel system to an enzyme electrode which is designed to carry out amultitude of measurements. The system described in this document andother systems based on electrochemical sensors that measurecontinuously, have the disadvantage that the sensors have a pronouncedsignal drift. This becomes particularly obvious from the document WO91/16416 when the laborious calibration is taken into consideration.Another disadvantage of such sensor-based systems is that relativelylarge amounts of fluids are required. In the prior art sensors are knownas systems that only require small amounts of liquid and thus thisstatement is initially surprising. However, when emphasising thepositive features of sensor systems, one often does not take intoaccount that fluid channels are necessary and a sensor surface ofsufficient size has to be wetted.

Ultrafiltration devices are also known in the prior art of which thedocuments U.S. Pat. No. 4,832,034 and U.S. Pat. No. 4,777,953 arementioned as examples. These systems also use electro-chemical sensorsand thus also have the above-mentioned disadvantages. In addition thereare disadvantages which are caused by the ultrafiltration membrane. Itis critical to select a suitable membrane material which has thecombined properties of an adequately high filtration effect andpermeability and does not already become blocked after a short period.

Another procedure for monitoring analyte concentrations is known underthe name microdialysis. Representative documents from this field are:U.S. Pat. No. 5,174,291, EP 0 401 179 and U.S. Pat. No. 4,265,249. Flowmeasuring cells with electrochemical sensors are used in thearrangements described in these documents. Although the ultrafiltrationproblems caused by membranes are less with microdialysis, microdialysissystems have the disadvantage that a perfusion liquid has to be pumpedthrough a hollow catheter. The provision of solutions, the pumpingprocess and the construction of the catheter are technical′complications which increase the complexity.

The methods described above for monitoring analyte concentrations inbody fluids are based on the premise that the monitoring requires acontinuous or at least a more or less continuous measurement atrelatively short time intervals. This explains the exclusive use ofsensors that operate continuously in flow measuring cells.

Discontinuous concepts are also known in the field of analyteconcentration monitoring. For example diabetics carry out severaldiscrete measurements during a day in order to monitor their bloodglucose level. For this purpose is it customary to firstly make anincision with a lancet and to apply the emerging blood to a disposabletest element. This is analysed with a suitable device in order todetermine the blood glucose concentration. Optical systems as well assystems that use electrochemical test elements are known in the priorart. Devices have also been known for some time in which the incision,sample collection and sample application can be carried out with asingle disposable test element. Such systems for determining bloodglucose in interstitial fluid are described for example in the documentsU.S. Pat. No. 5,746,217, U.S. Pat. No. 5,823,973 and U.S. Pat. No.5,820,570. The aforementioned devices have a thin cannula which isinserted into the dermis and collects interstitial fluid at this site.The cannula conveys the liquid onto a test element. A disadvantage ofthis system is that a cannula has to be inserted again for eachindividual measurement. In addition to the discomfort caused by therepeated piercing, the user has to carry out a number of operating stepssuch as inserting a disposable element into an apparatus, starting thelancing process, waiting until the result of the analysis is displayedand replacing the test element. Moreover the said devices have to becarried around by the user and he has to find a discreet place to carryout the measurement if he does not want to publicly exhibit his disease.

A system which also has the aforementioned disadvantages, but which usesa system comprising a catheter and an initially separate test element isdescribed in U.S. Pat. No. 5,368,029. According to this document acatheter is firstly introduced into a blood vessel and one waits until atransparent chamber is filled with blood (flushing). Then a disposabletest element is inserted into the chamber through a valve slit in orderto bring the test element into contact with the blood. It is hardlyconceivable that such a system could be used routinely by a diabeticsince it is necessary to introduce a catheter into a blood vessel with aconsiderable risk of infection and injury. In addition a relativelylarge amount of sample is required. The description in the documentshows that the system is designed to be used in emergency medicine.Another essential disadvantage of the concept is that the system doesnot enable monitoring of an analyte concentration but only allows asingle measurement which reflects the momentary concentration level. Thedocument contains no information or suggestions whatsoever on how tocarry out repeated measurements by coupling new test elements. This islogical since the blood collected in the chamber is not exchanged andthus subsequent measurements with additional test elements would onlyyield the same measured value and not a measured value that would leadto a later concentration value.

SUMMARY

The present invention is based on systems with sensors that operatecontinuously as well as on systems with separate lancing processes. Theinvention concerns a system for monitoring the concentration of analytesin body fluids, in particular in interstitial fluid and comprises acatheter with an implantable region and an outlet aperture forwithdrawing fluid, in particular body fluid. A first and a secondanalytical zone are contacted successively with fluid from the catheterand undergo a detectable change when an analyte is present. Thecontacting of the analytical zones with fluid can be achieved manuallyand also preferably automatically by means of a device. A systemaccording to the invention additionally has an analytical device toanalyse the analytical zones in order to determine the concentration ofthe analyte on the basis of the changes caused by the analyte. Thepresent invention additionally concerns catheters for use in systemsaccording to the invention and magazines with test zones.

The present invention combines the advantages of continuously operatingsystems with those of individual measurements using disposable testelements. The invention utilizes a catheter which remains implantedbetween the (at least two) measurements and hence it is not necessary tomake repeated incisions as is the case with previous systems withdisposable test elements. Problems of previous continuously operatingsystems which are mainly coupled to the use of continuously operatingsensors are avoided by using separate test elements. However, thiscombination of known elements has neither been previously described inthe prior art nor made obvious to a person skilled in the art.Previously experts have assumed that measurements have to be carried outat short time intervals for a continuous monitoring of the analyteconcentration which necessitates the use of flow measuring cellscontaining continuously operating sensor systems. Initially theprovision of such a large number of analyses at short time intervalsappears to be incompatible with disposable test elements. The conceptaccording to the invention revolutionizes the monitoring of analyteconcentrations because the monitoring can be carried out with arelatively simple system which is in particular free from the drift ofelectrochemical sensors. Dry chemistry test elements can be used for thetest elements or test zones which have already proven in practice to beparticularly suitable with regard to accuracy and precision and areadvantageous to manufacture.

The system and method according to the invention are used to monitoranalyte concentrations in body fluids. Analytes that can be monitoredusing the present invention are for example glucose, lactate,electrolytes, pharmaceutically active substances and such like. Bodyfluids in the sense of the invention are in particular interstitialfluid and blood. If interstitial fluid is used, fluid is preferred whichhas been obtained from a depth of >1 mm under the skin surface since atthis position there is a good and sufficiently fast exchange with theblood transport system.

A catheter with an implantable region is used to withdrawn fluid.Catheters within the sense of this invention are tubes into which thebody fluid enters and can be removed from an outlet opening and alsodevices with a semipermeable membrane and hence the fluid entering thecatheter is not a body fluid in a strict sense but a fluid that hasalready been pretreated (ultrafiltrate). In principle it is alsopossible to use a microdialysis catheter as a catheter which operateswith perfusion fluid and takes up analyte from the interior of the bodyby diffusion and yields dialysate. Catheters with a semipermeablemembrane or a microporous wall have the advantage that cells and evenlarger molecules interfering with detection may be excluded. It istherefore preferred to employ membranes or microporous walls with a poresize below 500 nm.

However, a problem with a microdialysis catheter circulating dialysisfluid is that fluid emerging from the catheter may under certaincircumstances not reflect the true analyte concentration inside the bodybut rather only a fraction thereof when the residence times are short.Consequently catheters are preferred for the invention which aredesigned such that body fluid flows directly out of them (as e.g. incase of ultrafiltration) which may also be freed from cells.

The term catheter is used in the scope of this invention not only forthe part that is implanted in the body but rather the term cathetershould also encompass the fluid connections and other connected partsthat belong to such a part. In the simplest case the catheter can becomposed of a thin hollow needle or a tubing one end of which isinserted into the body and from the other end of which, the outletopening, a body fluid flows out. Tubing or such like can be coupled tosuch a catheter so that as a result the outlet opening is shifted to thecorresponding end of the tubing. The structure and function of suitableor preferred catheters is described in more detail in conjunction withthe figures. It may be advantageous to use a so-called applicator deviceto insert the implantable region of the catheter into the body. In thismanner it is also possible to construct the implantable region with avery small diameter down to e.g. 100 μm. Even materials like steel areflexible in this thickness range. If an applicator device were not used,flexible constructions would have been eliminated for practical reasonsdue to the impossibility of introducing them into the body. Suitableapplicator devices for flexible and also for rigid arrangements areknown in the prior art. U.S. Pat. No. 3,651,807; EP A 0 366 336; WO95/20991 and WO 97/14468 are herewith referred to as examples wheresuitable applicator devices are described.

An additional feature of the invention is the use of two or moreanalytical zones which undergo a detectable change after contact withthe fluid taken from the outlet opening. Diverse forms of suitableanalytical zones are known from the field of disposable test elements.Analytical zones which undergo an optically detectable change areparticularly preferred in the scope of the invention for reasons whichwill be described in more detail. An embodiment of the analyticaldetection zone that is particularly preferred within the scope of theinvention is described in U.S. Pat. No. 6,029,919. With regard to thelayers of the test element it is of course also possible to use lesscomplex test elements. Electrochemical test elements can also be usedfor the invention. Electrochemical test elements such as those describedin U.S. Pat. No. 5,288,636 are advantageous compared to measuring cellsthat operate continuously like those used in the field ofultrafiltration and microdialysis since the drift problem is eliminated.

The use of the term “analytical zone” in contrast to “test element”makes it clear that the analytical zones do not necessarily have to beelements that are separated from one another but that the test zones canindeed be disposed on the same body (test element). In a particularlypreferred embodiment of the system according to the invention a tape isused in which the test chemistry is arranged in a band shape andadjacent regions of the tape can be contacted with fluid emerging fromthe catheter. This also makes it clear that the term analytical zone isnot limited to embodiments in which the analytical zones are predefinedbut that embodiments are particularly advantageous in which therespective analytical zone is not defined until contact with the fluid.As a result positioning problems can be largely circumvented. On theother hand it is, however, also possible to use test elements which areseparated from one another, each of which provides one or severalanalytical zones. As already elucidated it is preferred that disposableembodiments are used for the analytical zones in which an analyticalzone that has been used once is not used again. As already eluded to,the analytical zones of the present invention exhibit no drift like thatwhich occurs in the case of flow measuring cells. This is due to thefact that an unused analytical zone is employed and the properties ofthe analytical zones can be adequately controlled by the manufacturingprocess as is well-known in the prior art. As a result it is alsopossible to determine the manufacturing tolerances of the analyticalzones at the factory and to store these for example in the form of a barcode in order to increase the accuracy of the analysis by taking intoaccount these variations in the analytical process.

An important aspect of the present invention is a sequential applicationof liquid onto test zones in order to contact the test zones with liquidfrom the catheter. This can be achieved especially by bringing togethervarious analytical zones with the outlet opening of the catheter inorder to contact the analytical zones with fluid. Bringing together inthis sense primarily means moving the analytical zones to the outletopening so that they can take up fluid there. If, however, the outletopenings are located on a flexible tube it is possible to guide theoutlet opening to an analytical zone for the contacting. The term“bringing together” is also intended to encompass processes in whichanalytical zones for example in the form of a tape, are conveyed pastthe outlet opening, (while being in contact with the outlet opening orin direct proximity) in order to apply liquid to the analytical zones.

Embodiments are also possible in which liquid is already removed fromthe catheter by contact alone. This can be achieved in particular withabsorbent or capillary-active analytical zones. However, it isadvantageous to design the system such that liquid does not emerge fromthe outlet opening until an underpressure is applied. This enables theapplication of liquid on the analytical zone to be controlled byregulating the pressure conditions in the system.

Another method of contacting the analytical zones with liquid from thecatheter is to move the liquid out of the catheter in portions(dropwise) in such a manner that the fluid portions hit the test zones.This can be achieved in particular by using ink-jet or bubble-jetsystems in which the fluid portions are ejected from an outlet openingof the catheter or from a subsequent ejection unit. Reference is made tothe well-known printing technologies and to the document U.S. Pat. No.4,336,544 with regard to a possible design for such an ejection unit.

As already described in connection with U.S. Pat. No. 5,368,029, it isimportant for monitoring time-dependent changes of the analyteconcentration to ensure that liquid of a defined time range reaches ananalytical zone and that this liquid is mixed with the least possibleamount of liquid from previous time intervals. This can be achieved bythe present invention in a comparatively simple manner by using acatheter with an inner cross-section of less than about 0.5 mm. Withsuch small cross-sections there is almost no convection so that liquidmoves through the catheter in the form of a bolus. In this connection itis also important to avoid dead volumes in the catheter as far aspossible that are caused for example by back tapers at fluid junctionsetc. Another measure which is important in this connection relates tothe ratio between the volume of liquid that is removed from the catheterand the active inner volume of the catheter. The quantity of liquid thatis removed is preferably essentially the same as or larger than the.active catheter inner volume such that the active volume is essentiallycompletely emptied when liquid is removed for application onto ananalytical zone. This ensures, on the one hand, that the withdrawnliquid is derived from the time interval between the current withdrawaland the previous withdrawal. The active catheter inner volume refers tothe inner space of the catheter which fills with liquid between twoliquid withdrawals and which is emptied during a withdrawal. In additionto the geometric design of the catheter inner space, the active catheterinner volume is also determined by liquid barriers such as hydrophobicbarriers. Preferred designs of the catheter and the withdrawal processesare elucidated below on the basis of figures.

Another feature of the invention is an analytical device for analysingthe analytical zones after contact with liquid. Such analytical devicesare well-known in the prior art for example for blood sugar measuringinstruments. Reference is herewith made to the document U.S. Pat. No.4,852,025 as an example thereof in which transformation ofreflection-photometric measurements into concentration values isdescribed. Such an analytical device comprises a light source toilluminate an analytical zone, a detector to detect radiation reflectedfrom the analytical zone and an electronic circuit to convert thedetector signals into analyte concentrations. Such an analytical deviceor an additional application detection device can also advantageously beused to determine whether the analytical zone has been adequatelycontacted with liquid. However, it is not only possible to detectapplication of liquid as such onto an analytical zone as described forexample in EP 0 256 806 but it is also possible to relatively accuratelydetermine the amount of liquid with which the analytical zone has beenwetted. A detection of the wetting of an analytical zone is advantageouswithin the scope of the present invention for several reasons. On theone hand it enables a check of the operating sequence or even a controlof the sequence. In the case of systems which operate with anunderpressure to allow liquid to flow out of the outlet opening, thedetection of a wetting of or an adequate amount of liquid on theanalytical zone can for example be used as a signal to switch off theunderpressure and thus also the liquid transport. In addition this alsoenables this signal to be used to break the contact between theanalytical zone and liquid or outlet opening.

Detection of the application of liquid to an analytical zone ordetection of the amount of liquid that has been applied to an analyticalzone can be achieved in many ways. U.S. Pat. No. 5,114,350 for exampledescribes the monitoring of the surface reflection of a test zone. Asimilar procedure is also described in U.S. Pat. No. 4,199,261.Furthermore it is known from the document WO 83/00931 that absorbance ofradiation by the sample in the infrared range can be used as a measureof the quantity of liquid. The above-mentioned methods can be usedwithin the scope of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Construction of a catheter and mode of operation.

FIG. 2: Analytical system with a tape-shaped test element in aperspective view.

FIG. 3: Cassette with tape-shaped test element and catheter.

FIG. 4: Analytical system with a coupling to a tube system for bloodwithdrawal.

FIG. 5: Analytical system with separate units for manual operation.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1A shows the construction of a preferred catheter according to thepresent invention. The catheter comprises a hollow needle the distalpart (10) of which is implanted in the tissue (2) of a patient. Thehollow needle of FIG. 1 is manufactured from stainless steel and has anouter diameter of 500 pm, an inner diameter of 100 pm and a length of 7mm. Plastics can for example also be used instead of stainless steel. Aproximal region (11) with an enlarged inner cross section adjoins thedistal part of the hollow needle. As shown in FIG. 1A there is an outlettube (14) attached to an outlet opening (13) of the hollow needle thatis located slightly above the junction region between the implantedregion and the proximal region (11). The catheter arrangement isattached by a disk-shaped holder (15) to the body surface. For thispurpose the underside of the holder (15) can be provided with anadhesive. In order to further stabilize the arrangement, there is aconnecting element (16) above the holder (15) which ensures afluid-tight coupling of the outlet tube (14) to the outlet opening (13)of the hollow needle (10, 11).

The function of the catheter arrangement is made clear on the basis ofthe steps shown in figures A-D. Figure IA shows that body fluid, inparticular interstitial fluid, enters the implanted region (10) of thehollow needle and is conveyed by capillary forces or by vacuum into theproximal part of the hollow needle (11). In order to allow entry of bodyfluid, the implanted part (10) has one or several inlet openings (17).These can be located on the needle tip as well as in the wall region ofthe hollow needle located above this. The length of the implanted partand the position of the inlet openings can be used to determine fromwhich depth body fluid is conveyed. It has proven to be advantageous toconvey body fluids from depths of more than 1 mm. It was namely foundthat the upper skin layers (epidermis and dermis) which together have athickness of about 1 mm only weakly exchange substances with theinterior of the body and especially with the blood stream. It has nowbecome standard practice in diabetes monitoring to determine themetabolic state of the diabetic on the basis of the blood glucose value.This is especially due to the fact that the blood stream supplies thebrain and thus hypoglycemia can become an acute threat to life.Consequently it is preferred for the present invention to obtain sampleliquid from depths of more than 1 mm, preferably from a depth range of 3to 10 mm.

As shown in FIG. 1A the body fluid rises in the hollow needle and fillsthe proximal part (11) of the hollow needle. This usually takes placesolely by means of the capillary forces in the hollow needle. For thispurpose it is advantageous when the interior region of the hollow needlethat is to be wetted by sample liquid is made hydrophilic. In the caseof metallic hollow needles this can for example be achieved by applyinga hydrophilizing coating. If the capillary forces are not sufficient anunderpressure may be applied to convey body fluid from the interior ofthe body.

In FIG. 1A an air vent (12) is provided at the upper end of the hollowneedle which allows air displaced by the body fluid to escape. The airvent is preferably made hydrophobic to prevent body fluid from escapingfrom the hollow needle. The air vent can for example be a plastic tubemade from a hydrophobic polymer such as polyethylene. Another importantfunction of the air vent is to limit evaporation from the hollow needleto avoid blockage of the system by dried up liquid.

FIG. 1B shows the arrangement of FIG. 1A in a filled state ready for thedetermination. In particular it can be seen that firstly only theinterior space of the hollow needle has been filled but not theconnecting tube (14). This is achieved by using a connecting tube whichhas a hydrophobic (or hydrophobically coated) inner wall. Liquid iswithdrawn from the filled state of FIG. 1B as shown in figures C and D.Application of an underpressure at the outlet opening (14′) of theconnecting tube (14) empties the upper widened part of the hollow needle(proximal part 11). Preferably the fluid forces in the system areadjusted such that only the hollow space of the needle above the outletopening (13) is emptied. After this space has been emptied, air issucked in so that the body fluid is moved in the form of a bolus throughthe connecting tube onto a test zone which is contacted with the outletopening (14′). The liquid forms a spot (21) on the test zone (20) whichhas different optical properties than the surroundings and can thus bedetected. After the upper inner space of the needle has been emptied, itcan be slowly filled again with liquid which subsequently flows from theimplanted part. It was found that measurements at intervals of about 5minutes are completely adequate for monitoring the glucose concentrationin humans so that the time period required to fill the upper part of theneedle is relatively uncritical.

The system shown in FIG. 1 operates in a batch mode and the volumeprovided by one discharge can be adjusted by the volume in the upperneedle region (11). Alternatively liquid from an implanted needle can bedrawn up directly onto a test zone by for example contacting the testzone with an outlet opening.

FIG. 2 shows a system for monitoring concentrations which has ameasuring unit (101) and a disposable unit in which test zones arearranged in the form of a test element tape. The connecting tube (114)which can be coupled to the hollow needle as an alternative to theconnecting tube (14) in FIG. 1 is shown on the front side of thedisposable unit (121). The unit (121) is closed such that anunderpressure relative to the outer space can be applied to its innerspace via an underpressure connection (118). Two rollers are located inthe interior space of the unit (121), of which the first, the dispenserroller (119) carries a reel of tape-shaped analytical agent. The tape ispassed from the first roller (119) behind the outlet of the tube (114)and wound onto the second roller, the waste roller (120). The use of anabsorbent analytical tape is particularly advantageous within the scopeof the invention since liquid is taken up and absorbed which thus avoidscontamination of the interior space and also ensures a hygienic disposalof the fluids. In order to operate the roller mechanism the unit (121)has a rubber collar (122) in which a drive rod rotates which is drivenby the measuring unit (101) and which winds the analytical tap onto theroller (120) in a step-wise manner. The measuring unit (101) is equippedwith an optical head (102) which is inserted into a recess in thedisposable unit (121). The optical head (102) has a light source forilluminating the analytical tape and a detector to record the reflectedradiation. For this purpose an optical window (103) is provided on thefront side of the optical head (102). Since the analytical tape passesthrough a region that is closed to the external space and to whichunderpressure can be applied, a transparent window is provided in theunit (121) between the analytical tape and the optical head. Themeasuring unit also has an electronic analytical unit to determineanalyte concentrations based on the reflected radiation. The resultsthat are determined can for example be shown directly on a display orthey are passed onto a data processing unit (130) in order to bedisplayed or transmitted further. The measuring unit also has aconnection (105) for the tube (118) and a pump connected to theconnector which can be used to pump air out of the disposable unit(121). The measuring unit (101) additionally has a connector (104) forthe rubber flange (122) and a drive mechanism for a drive rod thatrotates in the flange. After the measuring unit and disposable unit hasbeen connected together and with a catheter, the analyte concentrationsare monitored as follows:

Underpressure is applied by the pump of the measuring unit to thedisposable unit (121) such that body fluid that has collected in thecatheter is sucked via the tube (114) into the unit (121) and passesonto the tape-like test element (analytical tape). After the fluid bolushas been applied to the test zone, the analytical optical system (102)is used to check whether the sample has been correctly applied to thetest zone on the basis of the wetted spot. A reflection photometricanalysis of the test zone is now carried out using the analytical optics(102) and the measurement result is converted into a concentration valuefor the analyte concentration. In the case of embodiments which do notoperate in a batch mode as described in connection with FIG. 1, theapplication of fluid on the test zone can also be monitored and when asufficient amount of fluid is detected, the contact between the testzone and fluid can be interrupted for example by releasing theunderpressure. Usually several minutes elapse after the measurement iscompleted until a short length of the tape-like test element is woundonto the waste roller (120) by actuating the drive mechanism and thus afresh test zone is moved to the vicinity of the outlet opening of thetube (114). Then liquid can be conveyed by again applying anunderpressure and can be taken up by the fresh analytical zone at theoutlet position of the tube (114).

FIG. 3 shows a disposable unit (121′) that is similar to the disposableunit shown in FIG. 2. The hollow needle (110′) that can be implanted inthe body is already integrated into this disposable unit. Theimplantable region (110′) is arranged perpendicular to the base surface(124′) of the disposable unit. As a result it is possible to implant thehollow needle (110′) directly in the body by pressing the base surfaceof the disposable unit on a body surface to simplify the handling. Thehollow needle (110′) is joined to the connecting tube (114′) which isheld by a holder (125′). The tape-like test element (108′) is guidedpast the outlet site of the connecting tube (114′) to yield the sampleapplication spot (140) at this position. The analytical tape is guidedthrough rollers (126′). If one measurement is carried out every 5minutes a 100 cm long analytical tape (108′) enables the analyteconcentration to be monitored over a period of about 24 hours. In orderto prevent ageing of the analytical tape (108′) during this period, adesiccant (127′) can be provided in the disposable unit (121′). Also dueto the ageing of the analytical material it is preferable to seal andstore the disposable units (121/121′) in a water-tight and vapour-tightmanner before use. This can be achieved in a simple manner by sealingthe disposable units after manufacture in a plastic laminate.

FIG. 4 shows a system for monitoring analyte concentrations which canfor example be used in the field of emergency medicine. In this field itis usual to place a catheter in a blood vessel in order to withdrawblood to monitor analyte concentrations or to administer medicines. Whena blood stream is withdrawn via a fluid line (200), a system can becoupled to it so that the analyte concentration can be monitoreddirectly in the blood. A T-piece (201) can be provided for this viawhich blood is withdrawn using the withdrawal tube (114″). Themonitoring process is similar to that described in the previous figures.However, with the system shown withdrawal is made directly from theblood stream without the batch-wise filling and emptying of a hollowspace of a predetermined volume as in FIG. 1.

FIG. 5 shows an embodiment of a monitoring system that is integrated toa lesser degree. The unit (301) carried on the body comprises a catheter(310) that can be implanted in body tissue (2) which is held in a plate(315) that is attached to the body. A holder (302) for test elementswith a receiving opening (303) is located above the catheter opening.When a first test element (320) is inserted, the analytical zone (321)is placed above the catheter opening and body fluid emerging from thecatheter wets the analytical zone. When a sufficient amount of bodyfluid has been applied to the test zone which an for example be visuallydetected by the user, the test element is inserted manually into aconventional analytical instrument (400) and analysed there. As soon asan additional measurement is required, the user can insert a second testelement (320′) into the opening (303) to wet the test zone (321′).Although the user has to carry out more steps on his own than is thecase with a system shown in the previous figures, the embodiment of FIG.5 has an extremely simple construction and it is possible to usecommercially available units for test elements and analyticalinstruments. A major advantage of the system of FIG. 5 compared toprevious commercial systems is that the operator does not have torepeatedly pierce his body for the individual withdrawals of body fluid,but instead the unit (301) provides the necessary body fluid for theanalyses as required.

1. System for monitoring the concentration of analytes in body fluids,comprising a) a catheter having an implantable region and an outletopening for the withdrawal of fluid, b) a first and a second analyticalzone which, after contact with the withdrawn fluid, undergo a detectablechange when an analyte is present in the fluid, c) a device configuredto contact the first analytical zone with fluid from the catheter and tosubsequently contact the second analytical zone with fluid from thecatheter, d) an analytical device configured to analyze the changes onthe analytical zones caused by the analyte-containing fluid in order todetermine the concentration of an analyte to be monitored, and e) a pumpconfigured to apply underpressure to the outlet opening in order toconvey liquid, wherein the analytical device or an additionalapplication detection device detects the presence of fluid or thepresence of an adequate amount of fluid in or on the analytical zonesand interrupts the application of the underpressure to the outletopening based thereon, and wherein the first and second analytical zonesare areas of a continuous test element, and the continuous test elementis a tape.
 2. System as claimed in claim 1, wherein the device isconfigured to contact the first analytical zone and the secondanalytical zone with the fluid from the catheter by bringing togetherthe outlet opening and the first and second analytical zones.
 3. Systemas claimed in claim 1, wherein the device is configured to contact thefirst analytical zone and the second analytical zone with the fluid fromthe catheter by moving portions of the fluid out of the catheter ontothe first and second analytical zones via an ejector unit.
 4. System asclaimed in claim 1, in which the first and second analytical zones areseparate objects that are attached to a common support.
 5. System asclaimed in claim 1, in which the catheter is designed such that noliquid emerges from the outlet opening until the underpressure isapplied to the outlet opening.
 6. System as claimed in claim 1, furthercomprising a control device which synchronizes the bringing together ofthe first and second analytical zones with the outlet opening.
 7. Systemas claimed in claim 1, in which the amount of fluid taken up by eitherof the first and second analytical zones is essentially equal to or morethan the active inner volume of the catheter.
 8. System as claimed inclaim 1, wherein the device is configured to contact the firstanalytical zone and the second analytical zone with the fluid from thecatheter while the catheter remains implanted.
 9. System as claimed inclaim 1, wherein the analytical zones are configured to be used once.10. System as claimed in claim 1, in which the system further comprisesa carrying unit for carrying the system on the body and a magazine inwhich the analytical zones are disposed and which is configured to beinserted into the carrying unit.
 11. System as claimed in claim 1, inwhich the amount of fluid taken up by an analytical zone is less than100 nl.
 12. System as claimed in claim 1, in which the analytical deviceis configured to optically analyze the first and second analyticalzones.
 13. The system of claim 1, wherein the fluid is an interstitialbody fluid.
 14. A system for monitoring the concentration of analytes inbody fluids, the system comprising: a) a catheter having an implantableregion and an outlet opening for the withdrawal of fluid, b) a first anda second analytical zone which, after contact with the withdrawn fluid,undergo a detectable change when an analyte is present in the fluid, c)a device configured to contact the first analytical zone with fluid fromthe catheter and to subsequently contact the second analytical zone withfluid from the catheter, d) an analytical device configured to analyzethe changes on the analytical zones caused by the analyte-containingfluid in order to determine the concentration of an analyte to bemonitored, and e) a pump configured to apply underpressure to the outletopening in order to convey liquid, wherein the device is configured tocontact the first analytical zone and the second analytical zone withthe fluid from the catheter in synchronization with the application ofthe underpressure such that liquid emerging from the outlet opening istaken up by the analytical zones, and wherein the first and secondanalytical zones are areas of a continuous test element, and thecontinuous test element is a tape.
 15. System as claimed in claim 14, inwhich the analytical device or an additional application detectiondevice is configured to detect the presence of fluid or the presence ofan adequate amount of fluid in or on the analytical zones and tointerrupt further contact of the analytical zones with fluid.
 16. Asystem for monitoring analyte concentration in body fluid comprising, acarrying unit configured to be carried on the body, the carrying unithaving a catheter comprising an implantable region and an outlet openingfor withdrawing fluid and a tape comprising two or more analytical zoneswhich undergo a detectable change when an analyte is present in thefluid, and a device configured to contact the fluid with the two or moreanalytical zones while the catheter remains implanted, and an analyticaldevice located in the carrying unit or present separately and configuredto analyze changes caused by the analyte-containing fluid on the two ormore analytical zones in order to determine the concentration of theanalyte.
 17. The system as claimed in claim 16, wherein the two or moreanalytical zones comprise at least a first analytical zone and a secondanalytical zone, and wherein the device is further configured to eitherbring together the first analytical zone with the outlet opening inorder to contact the first analytical zone with fluid and tosubsequently bring together the second analytical zone with the outletopening in order to contact the second analytical zone with fluid, or toapply underpressure to the outlet opening to convey the fluid such thatfluid emerging from the outlet opening contacts the first analyticalzone and the second analytical zone in synchronization with theapplication of the underpressure.